Recently, highly biocompatible polymers have been formulated to provide implantable medical devices with coatings. These coatings not only increase an implant's tissue compatibility but can also function as bioactive agent reservoirs. However, designing polymer coatings for medical devices has proven problematic. Medical device coatings must be non-toxic, durable and adhere well to device surfaces. Additionally, when the medical device comes into intimate contact with tissues such as blood and internal organs it must also be biocompatible. Furthermore, if the medical device is designed to be pliable either in operation or deployment, the coating must resist cracking, fracture and delamination.
Moreover, polymer coatings on medical devices intended to act as bioactive agent (drug) eluting devices must not only be biocompatible, structurally stable, resistant to delamination, but also chemically compatible with the drug to be administered. Furthermore, if the coating is also intended to control the drug's release rate into adjacent tissue the polymer used must possess other highly specialized properties as well such as, but not limited to appropriate glass transition temperatures and appropriate hydrophilicity/hydrophobicity indexes.
One of the most widely used techniques to modify the properties of a polymer material is to blend different polymers or copolymers together into a single mixture. The resulting polymer mixtures possess a combination of properties of each polymer or copolymer component of the blend. Not all polymers, however, are miscible and thus instead of forming a uniform blend, the polymers can form immiscible mixtures subject to phase separation and delamination. When used as coatings for medical devices this problem becomes even more pronounced. One polymer component may have a stronger affinity for the medical device surface than another and thus may layer closer to the medical device surface. The polymer component having less affinity and avidity for the medical device surface migrates away from the medical device surface resulting in a bi-layer where each polymer component retains its individual properties and the coating no longer functions as a cohesive uniform substance. When bioactive agents are included in the mixture, the problems associated with immiscibility are magnified by the addition of yet a third chemical species having unique chemical properties. An additional variable is introduced by the material of the medical device substrate.
Thus, prior art methods used to develop polymer coatings, specifically drug-eluting coatings, have been largely by trial and error. Recently, the present inventors have developed methods for reducing uncertainty in coating design by matching polymer components with bioactive agents based, in part, on solubility factors. While these procedures have significantly advanced polymer coating science, the primary focus of this disclosure is directed at polymer block copolymers.
Block copolymers are important polymer compositions for use as medical device coatings and as drug-eluting reservoirs as well as fabricating medical devices. Block copolymers are copolymers having individual subunits integrated into a single macromolecule. Different compositions in the polymers will yield different physical properties that can be advantageous to various medical applications. Consequently these are stable compounds not prone to delaminate or separate. Moreover, pendent R groups present within each block can be modified to increase or decrease overall polymer miscibility with bioactive agents without adversely affecting the polymer's structural performance characteristics. Unfortunately, block copolymers are very difficult to synthesize and thus, to date, there are only a limited number of polymers commercially available for medical use. Recent advances in synthetic chemistry, however, have led to the development of new methods for free radical polymerization; specifically atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT). These new synthetic methods can provide for the convenient synthesis of a wide range of block copolymers that were previously impossible or difficult to make.
U.S. Pat. No. 6,855,770 B2 (hereinafter the '770 patent) issued Feb. 15, 2005 to Pinchuck et al. describe certain medical grade block copolymers useful for drug delivery. The '770 patent discloses a block copolymer comprising one or more elastomeric blocks and one or more thermoplastic blocks combined with a therapeutic agent, specifically a polystyrene-polyisobutylene-polystyrene copolymer combined with paclitaxel and used to coat a vascular stent. The block copolymers in the '770 patent are made using carbocationic polymerization (living ionic polymerization) and synthesis is conducted under conditions that minimize or avoid chain transfer termination of the growing chain. However, these prior art methods are very susceptible to attack, and thus termination, by active hydrogens; consequently water, alcohol and the like must be kept to a minimum. This limitation in prior art methods significantly limits the range of solvents and hydrocarbons that can be used. These limited reaction conditions and monomer subunit selections leads to a narrow range of polymer types and thus restricted compatibility with diverse bioactive agents.
Thus, there is a need for improved polymeric materials suitable for coating implantable medical devices. Therefore, it is an object of the present invention to provide compositions and associated methods for a wide range of biocompatible block copolymers, useful for coating and forming implantable medical devices.